Heterocellular OSM-OSMR signalling drives pancreatic tumour growth and metastasis through functional fibroblast reprogramming

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterised by a pathologicalfibroinflammatorymicroenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however thedisparate effect of individual stromal subsets remains incompletely characterised. Here, we describe how heterocellular OSM-OSMR signalling instructsfibroblast reprogramming,tumourgrowth and metastasis.Macrophage-secreted OSM stimulatesinflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumorigenic environment and engage tumour cellsurvival and migratory signalling pathways. Tumour cells implanted in Osm-deficient (Osm-/-) mice display an epithelial-dominated morphology, reduced tumour growth and did notmetastasise. Moreover, the tumour microenvironment of Osm-/-animals exhibit increased abundance of αSMAposmyofibroblasts and a shift in myeloid and T cell phenotypes, consistent with a more immunogenic environment. Taken together, these data demonstrate how OSM-OSMR signalling coordinates heterocellular interactions to drive a pro-tumorigenic environment in PDA.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Pancreas

DISEASE(S): Pancreatic Ductal Carcinoma

SUBMITTER: Brian Lee  

LAB HEAD: Claus Jorgensen

PROVIDER: PXD022484 | Pride | 2021-11-29

REPOSITORIES: Pride